He only threw six innings for the short seasonBatavia Muckdogs due to shoulder tendinitis. The Phillies released him a week before the start of the 2004 season because they felt he was not good enough to pitch in Low-A and too old to return to short season ball.[1]

After a solid season helping Modesto to the league playoffs, while pitching in his first game in the playoffs, Ziegler was hit in the head by a line drive off the bat of Fred Lewis, playing for the San Jose Giants at the time. Ziegler suffered a fracture of the skull but recovered in time to pitch again in 2005, earning a promotion to the Double-A Midland RockHounds of the Texas League.

Before the start of the 2007 season, Ziegler was approached by Ron Romanick, the minor league pitching coordinator for the Athletics, about converting to a sidearm/submarine style of pitching. He agreed to the change and spent the 2007 season in both Midland and Sacramento as a relief pitcher, improving the more he became accustomed to the change.

This led to a strong start to the 2008 season in Sacramento prior to joining the major league club, though he suffered a second fracture of the skull in January during a workout following a youth camp he was assisting with. A thrown baseball deflected off another glove, hitting him in the forehead. Again, Ziegler recovered with no negative long-term effects.

Ziegler received his first call-up to the major leagues on May 30, 2008, when the Athletics purchased his contract from the Triple-A Sacramento River Cats. In 19 relief appearances with the River Cats before his promotion, Ziegler was 2-0 with a 0.37 earned run average. He had allowed just one earned run on 15 hits in 24.1 innings, while striking out 20. He earned his first Major League win on June 8 against the Los Angeles Angels of Anaheim.

Ziegler picked up his first career save in the major leagues and become the Athletics new closer on August 8 against the Detroit Tigers.[4] In earning his second on August 12 against the Tampa Bay Rays, he established a new Oakland record for consecutive scoreless innings at any point in a career with 38, passing starting pitcher Mike Torrez, who reached 37 in 1976.[5]

Ziegler's streak came to an end at 39 innings when the Tampa Bay Rays scored a run against him in the ninth inning on August 14. Akinori Iwamura scored on a double by B.J. Upton, which was also the first extra base hit Ziegler had allowed in the Majors. He had tied Al Benton after a scoreless eighth inning, finishing at 39. Benton did it in 1949 with the Cleveland Indians, though he allowed runs during that stretch as a starter. Ziegler also tied Christy Mathewson for second place for scoreless innings by a rookie. Mathewson's streak came in 1901 as a member of the New York Giants. Grover Cleveland Alexander holds the record for a rookie, throwing 41 consecutive scoreless innings in 1911 with the Philadelphia Phillies.

On July 31, 2011, Ziegler was traded to the Arizona Diamondbacks for Brandon Allen and Jordan Norberto.[6] On December 20, 2013, the Diamondbacks reported they had reached an agreement for a 2-year contract, worth 10.5 million dollars with Ziegler. The right-handed reliever will get $4.5 million for 2014 and $5 million for 2015 with a $5.5 million option for 2016, including a $1 million buyout.[7] On November 3, 2015, the Diamondbacks exercised Ziegler's 2016 option.[8]